Restoration of Missing MicroRNAs Blocks Spread of Pancreatic Cancer

Cancer researchers have found that an overexpressed oncogene in pancreatic tumor cells inhibits the production of a class of microRNAs (miRNAs) that would normally control the oncogene's activity.

An oncogene known as RAS, a member of the KRAS family of oncogenes is mutated and overexpressed in most types of human pancreatic cancer. What has not been clear is how the oncogene avoids normal cellular control mechanisms.

In the current study, however, investigators at Johns Hopkins University (Baltimore, MD, USA) have identified a direct link between RAS activity and the production of two miRNA's, miRNA-143 and miRNA-145. The repression of these miRNAs was seen in cells of human, mouse, and zebrafish origin. In particular, it was seen that human pancreatic cancer cells with RAS mutation had much lower miR-143/145 activity than did normal pancreatic cells.

In their paper published in the December 15, 2010, issue of the journal Genes and Development, the investigators showed that restoring the normal levels of miRNA-143/145 in cultures of pancreatic tumor cells prevented them from further uncontrolled cell division. Testing this finding in an animal model, the investigators found that when human pancreatic cancer cells with low levels of miRNA 143/145 were injected into mice, they formed tumors within 30 days. However, if the injected tumor cells contained microRNA levels equivalent to that of normal cells, tumors failed to form.

"Our finding that these specific microRNAs are downstream of the most important oncogene in pancreatic cancer sets the stage for developing methods to deliver them to tumors,” said senior author Dr. Josh Mendell, associate professor of genetic medicine at Johns Hopkins University. "When we restore microRNAs to cancer cells in which their levels are repressed, the cells no longer are tumorigenic. We have every reason to believe that the efficient delivery of miR-143/145, if achievable, would be therapeutically beneficial. There is a lot of work going on to develop ways to deliver microRNAs to different tissue sites, and I am optimistic that the liver and even the pancreas will become accessible to these types of therapies and benefit from them.”

"We need a better understanding of their basic functions to more fully understand how microRNAs participate in diseases,” said Dr. Mendell. "It is likely that some microRNAs will have very broad antitumorigenic effects in many different types of cancers. In fact, there is already evidence that miR-143/145 can suppress other types of tumors such as colon and prostate cancer. On the other hand, the effects of some microRNAs will likely be very tumor-specific.”

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